1.血清半乳甘露聚糖检测对血液病患者侵袭性曲霉菌感染的早期诊断研究 2.异基因造血干细胞移植后侵袭性真菌感染及其危险因素分析
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摘要
【目的】
初步评价血清半乳甘露聚糖(GM)浓度测定对血液病患者侵袭性曲霉菌感染(IA)中的早期诊断价值。
【方法】
采用双抗体夹心酶联免疫吸附分析(ELISA)法测定72例血液病患者的96份血清样本的GM浓度,根据我国侵袭性真菌感染诊断标准,评价GM测定前后诊断的变化,并计算该诊断试验的各项评价指标。
【结果】
按照试验中测定的界值,该诊断试验的灵敏度为82.3%,特异度为88.7%,阳性预测值为86.8%,阴性预测值为87.2%。GM测定阳性为22例,GM测定阴性为50例,通过GM测定临床诊断IA者由19例增加至28例,且GM浓度与患者疾病的预后具有相关性。
【结论】
通过ELISA方法进行血清GM检测可以为早期诊断IA提供有力证据,是一项快速、较灵敏的诊断试验。
【目的】
本研究分析异基因造血干细胞移植(Allo-HSCT)后患者侵袭性真菌感染(IFI)的发生及其高危因素。
【方法】
选择自2000年1月至2007年3月在我院行异基因HSCT患者180例,随访至2007年10月31日,用Kaplan—Meier和Cox回归模型方法,分析了IFI的发生率及其相关的危险因素。
【结果】
35例(19.5%)患者在HSCT后发生了IFI,确诊1例,临床诊断34例;其中曲霉菌感染18例(51.4%),念珠菌感染17例(48.6%)。IFI组1年的存活率为34.3%,无IFI组1年的存活率为53.8%,存在显著性差异。在单因素分析中,与IFI的发生率增加有关的包括:移植前真菌定植或感染、无关供者移植、急性GVHD发生、广泛性慢性GVHD、应用甲强龙。在多因素分析时,非血缘供者异基因外周血或骨髓干细胞移植、急性GVHD发生及移植前真菌感染或定植使IFI发生危险增加(RR分别为:1.589、2.399、1.410)。
【结论】
IFI是异基因HSCT的常见并发症,也是主要致死原因之一。对移植前真菌感染或定植、非血缘供者异基因外周血或骨髓干细胞移植及发生急性GVHD的高危患者有必要早期采取干预性治疗。
Objective To evaluate the value of serum galactomannan(GM) detection for early diagnosis of invasive aspergillosis(IA) in patients with hematological disease.
Methods The serum GM concentration in 96 sera from 72 patients was detected by Platelia Aspergillus double-sandwich enzyme linked immunosorbent assay(PADSELISA).According to the diagnostic criteria of invasive fungal infections in China,the diagnostic changes were evaluated,the sensitivity, specificity and predictive values were calculated.
Results The sensitivity and specificity of the PADSELISA were 82.3%and 88.7%and the positive and negative predictive values were 86.8%and 87.2%respectively.There were 22 positive cases,and 50 negative cases,and the probable IA cases were increased from 19 to 28 after the GM detection.Moreover,the serous level of galactomannan was correlated with the prognosis of the IA.
Conclusions The PADSELISA for GM detection is a reliable method for early diagnosis and treatment of IA in patients with hematological disease.
Objective In order to analyze the incidence and high-risk factors of invasive fungal infections among recipients of allogeneic hematopoietic stem cell transplantation (alIo-HSCT).
Methods 180 cases of allo-HSCr were enrolled in this study. The incidence and risk factors of IFI were analyzed by method of Kaplan-meier and Cox regression model.
Results An incidence of 19.5%of IFI in 35 cases were detected, with 1 case proven and 34 cases probably diagnosed,which was composed of 18 cases(51.4%) of aspergillosis and 17 cases(48.6%) of candidosis.There was significant difference in one-year overall survival rate between patients with(34.3%) or without(53.8%) IFI.In univariate analysis,risk factors of IFI included:pretransplant fungal infection or colonization, unrelated donor(peripheral blood or bone marrow stem cell) transplantation,acute GVHD,extensive chronic GVHD and the use of methylprednisolone.In multi-variate analysis,the following risk factors of IFI were found:unrelated donor for allogeneic peripheral blood or bone marrow stem cell transplantation,acute GVHD and pretransplant fungal infection or colonization acute GVHD(RR:2.399,1.589,and 0.836).
Conclusions It is concluded that IFI is a frequent complication and one of the leading causes of mortality among recipients of allo-HSCT.As for patients with higher risk of IFI,early interventions should be taken.
初步评价血清半乳甘露聚糖(GM)浓度测定对血液病患者侵袭性曲霉菌感染(IA)中的早期诊断价值。
【方法】
采用双抗体夹心酶联免疫吸附分析(ELISA)法测定72例血液病患者的96份血清样本的GM浓度,根据我国侵袭性真菌感染诊断标准,评价GM测定前后诊断的变化,并计算该诊断试验的各项评价指标。
【结果】
按照试验中测定的界值,该诊断试验的灵敏度为82.3%,特异度为88.7%,阳性预测值为86.8%,阴性预测值为87.2%。GM测定阳性为22例,GM测定阴性为50例,通过GM测定临床诊断IA者由19例增加至28例,且GM浓度与患者疾病的预后具有相关性。
【结论】
通过ELISA方法进行血清GM检测可以为早期诊断IA提供有力证据,是一项快速、较灵敏的诊断试验。
【目的】
本研究分析异基因造血干细胞移植(Allo-HSCT)后患者侵袭性真菌感染(IFI)的发生及其高危因素。
【方法】
选择自2000年1月至2007年3月在我院行异基因HSCT患者180例,随访至2007年10月31日,用Kaplan—Meier和Cox回归模型方法,分析了IFI的发生率及其相关的危险因素。
【结果】
35例(19.5%)患者在HSCT后发生了IFI,确诊1例,临床诊断34例;其中曲霉菌感染18例(51.4%),念珠菌感染17例(48.6%)。IFI组1年的存活率为34.3%,无IFI组1年的存活率为53.8%,存在显著性差异。在单因素分析中,与IFI的发生率增加有关的包括:移植前真菌定植或感染、无关供者移植、急性GVHD发生、广泛性慢性GVHD、应用甲强龙。在多因素分析时,非血缘供者异基因外周血或骨髓干细胞移植、急性GVHD发生及移植前真菌感染或定植使IFI发生危险增加(RR分别为:1.589、2.399、1.410)。
【结论】
IFI是异基因HSCT的常见并发症,也是主要致死原因之一。对移植前真菌感染或定植、非血缘供者异基因外周血或骨髓干细胞移植及发生急性GVHD的高危患者有必要早期采取干预性治疗。
Objective To evaluate the value of serum galactomannan(GM) detection for early diagnosis of invasive aspergillosis(IA) in patients with hematological disease.
Methods The serum GM concentration in 96 sera from 72 patients was detected by Platelia Aspergillus double-sandwich enzyme linked immunosorbent assay(PADSELISA).According to the diagnostic criteria of invasive fungal infections in China,the diagnostic changes were evaluated,the sensitivity, specificity and predictive values were calculated.
Results The sensitivity and specificity of the PADSELISA were 82.3%and 88.7%and the positive and negative predictive values were 86.8%and 87.2%respectively.There were 22 positive cases,and 50 negative cases,and the probable IA cases were increased from 19 to 28 after the GM detection.Moreover,the serous level of galactomannan was correlated with the prognosis of the IA.
Conclusions The PADSELISA for GM detection is a reliable method for early diagnosis and treatment of IA in patients with hematological disease.
Objective In order to analyze the incidence and high-risk factors of invasive fungal infections among recipients of allogeneic hematopoietic stem cell transplantation (alIo-HSCT).
Methods 180 cases of allo-HSCr were enrolled in this study. The incidence and risk factors of IFI were analyzed by method of Kaplan-meier and Cox regression model.
Results An incidence of 19.5%of IFI in 35 cases were detected, with 1 case proven and 34 cases probably diagnosed,which was composed of 18 cases(51.4%) of aspergillosis and 17 cases(48.6%) of candidosis.There was significant difference in one-year overall survival rate between patients with(34.3%) or without(53.8%) IFI.In univariate analysis,risk factors of IFI included:pretransplant fungal infection or colonization, unrelated donor(peripheral blood or bone marrow stem cell) transplantation,acute GVHD,extensive chronic GVHD and the use of methylprednisolone.In multi-variate analysis,the following risk factors of IFI were found:unrelated donor for allogeneic peripheral blood or bone marrow stem cell transplantation,acute GVHD and pretransplant fungal infection or colonization acute GVHD(RR:2.399,1.589,and 0.836).
Conclusions It is concluded that IFI is a frequent complication and one of the leading causes of mortality among recipients of allo-HSCT.As for patients with higher risk of IFI,early interventions should be taken.
引文
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42.中华内科杂志编辑委员会.血液病/恶性肿瘤患者侵袭性真菌感染的诊断标准与治疗原则(草案).中华内科杂志,2005.44:554-556.
43.Winston DJ,Maziarz RT,Chandrasekar PH,et al.Long-term antifungal prophylaxis in allogeneic bone marrow transplant patients:a multieenter,randomized trial of intravenous /oral itraconozole Versus intravenous/oral fluconazole.Ann lnten.2003.138:705-713.
44.Mattiuzzi GN,Kantariian H,Alvarado G,et al.Intravenous itraconazole VS caspofungin prophylaxis in patients with acute myelogenous leukemia and myelodysplastic syndrome undergoing induetion chemotherapy.In:43rd ICAAC abstracts.AmericanSociety for Microbiology,2003:45 1.
45.Marr KA,Seidel K,Slavin MA,et al.Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized,placebo-controlled trial. Blood. 2000 Sep 15; 96(6):2055-61.
46. Winston DJ, Maziarz RT, Chandrasekar PH, et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients.A multicenter, randomized trial. Ann Intern Med. 2003 May 6;138(9):705-13.
47. Marr KA, Crippa F, Leisenring W, et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood. 2004 Feb 15;103(4):1527-33.
48. Stute N, Kratochwille A, ZabelinaT, et al. Caspofungin is highly effective as secondary prophylaxis in allogeneic stem cell transplantation in patients with prior systemic or invasive fungal infections. In: Proceedings 45th ASH,2003: 3636.
49.Comely OA, Bethe U, Cesaro S, et al. Detection of predictor variables for breakthrough invasive fungal infection during secondary prophylaxis: results from a European registry. In: 43~(rd) ICAAC Abstracts. American Society for Microbiology ,2003: 456.
50. Allinson K, Kolve H, Gumbinger HG, Vormoor HJ, Ehlert K,Groll AH. Secondary antifungal prophylaxis in paediatric allogeneic haematopoietic stem cell recipients.J Antimicrob Chemother. 2008 Mar;61 (3) :734-42. Epub 2008 Jan 31.
51.Boogaerts M, Winston DJ, Bow EJ, et al. Intravenous and Oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving bmad——spectrum antibaet.erial therapy: a randomized controlled trial. Ann Intern Med, 2001, 135: 412—422.
52. Bow EJ. Of yeasts and hyphae: a hematologist's approach to antifungal therapy. Hematology Am Soc Hematol Educ Program.2006;:361-7.
53. Maertens J, Theunissen K, Verhoef G, et al. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis. 2005 Nov 1;41(9):1242-50.
54. Caillot D, Thiebaut A, Herbrecht R et al. Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies:arandomized pilot study (COMBISTRAT trial). Cancer 2007; 110:2740 - 2746.
55. Kontoyiannis DP, Boktour M, Hanna H, Torres HA, Hachem R,Raad II. Itraconazole added to a lipid formulation of amphotericin B does not improve outcome of primary treatment of invasive aspergillosis. Cancer 2005; 103: 2334-2337.
56.Popp AI, White MH, Quadri T, Walshe L, Armstrong D. Amphotericin B with and without itraconazole for invasive aspergillosis: a three-year retrospective study. Int JInfect Dis 1999; 3: 157-160.
57.Wtdsh TJ, Patterson T, Langston A, et al. Posaeonazole for treatment of invasive aspergillosis in patients who are refractory to or intolerant of conventional therapy: an externally controlled blind trial (abstract) . In :Proceedings 45th ASH, 2006: 682.
58. Raad II, Hanna HA, Boktour M, et al. Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin. Leukemia. 2008 Mar;22(3): 496-503.
59. Alves SH, Da Matta DA, Azevedo AC, et al. In vitro activities of new and conventional antimycotics against fluconazole-susceptible and non-susceptible Brazilian Candida spp. isolates. Mycoses. 2006 May;49(3) : 220-5.。
60. Pasqualotto AC, Denning DW. New and emerging treatments for fungal infections. J Antimicrob Chemother. 2008 Jan;61 Suppl 1:119-30.
61.Mycamine (micafungin) [package insert]. Deerfield,IL:Astellas Pharma US Inc; 2006.
62.Eraxis (anidulafungin) [package insert]. New York,NY:Pfizer Inc;2007.
63. Pasqualotto AC, Denning DW. New and emerging treatments for fungal infections. JAntimicrob Chemother. 2008 Jan;61 Suppl
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40.Bow EJ,Laverdiere M,Lussier N,et al.Antifungal prophylaxis for severely neutropenic chemotherapy recipients:a meta analysis of randomized-controlled clinical trials.Cancer.2002 Jun 15;94(12):3230-46.
41.Robenshtok E,Gafter-Gvili A,Goldberg E,et al.Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation:systematic review and meta-analysis.J Clin Oncol.2007 Dec 1:25(34):5471-89.
42.中华内科杂志编辑委员会.血液病/恶性肿瘤患者侵袭性真菌感染的诊断标准与治疗原则(草案).中华内科杂志,2005.44:554-556.
43.Winston DJ,Maziarz RT,Chandrasekar PH,et al.Long-term antifungal prophylaxis in allogeneic bone marrow transplant patients:a multieenter,randomized trial of intravenous /oral itraconozole Versus intravenous/oral fluconazole.Ann lnten.2003.138:705-713.
44.Mattiuzzi GN,Kantariian H,Alvarado G,et al.Intravenous itraconazole VS caspofungin prophylaxis in patients with acute myelogenous leukemia and myelodysplastic syndrome undergoing induetion chemotherapy.In:43rd ICAAC abstracts.AmericanSociety for Microbiology,2003:45 1.
45.Marr KA,Seidel K,Slavin MA,et al.Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized,placebo-controlled trial. Blood. 2000 Sep 15; 96(6):2055-61.
46. Winston DJ, Maziarz RT, Chandrasekar PH, et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients.A multicenter, randomized trial. Ann Intern Med. 2003 May 6;138(9):705-13.
47. Marr KA, Crippa F, Leisenring W, et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood. 2004 Feb 15;103(4):1527-33.
48. Stute N, Kratochwille A, ZabelinaT, et al. Caspofungin is highly effective as secondary prophylaxis in allogeneic stem cell transplantation in patients with prior systemic or invasive fungal infections. In: Proceedings 45th ASH,2003: 3636.
49.Comely OA, Bethe U, Cesaro S, et al. Detection of predictor variables for breakthrough invasive fungal infection during secondary prophylaxis: results from a European registry. In: 43~(rd) ICAAC Abstracts. American Society for Microbiology ,2003: 456.
50. Allinson K, Kolve H, Gumbinger HG, Vormoor HJ, Ehlert K,Groll AH. Secondary antifungal prophylaxis in paediatric allogeneic haematopoietic stem cell recipients.J Antimicrob Chemother. 2008 Mar;61 (3) :734-42. Epub 2008 Jan 31.
51.Boogaerts M, Winston DJ, Bow EJ, et al. Intravenous and Oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving bmad——spectrum antibaet.erial therapy: a randomized controlled trial. Ann Intern Med, 2001, 135: 412—422.
52. Bow EJ. Of yeasts and hyphae: a hematologist's approach to antifungal therapy. Hematology Am Soc Hematol Educ Program.2006;:361-7.
53. Maertens J, Theunissen K, Verhoef G, et al. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis. 2005 Nov 1;41(9):1242-50.
54. Caillot D, Thiebaut A, Herbrecht R et al. Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies:arandomized pilot study (COMBISTRAT trial). Cancer 2007; 110:2740 - 2746.
55. Kontoyiannis DP, Boktour M, Hanna H, Torres HA, Hachem R,Raad II. Itraconazole added to a lipid formulation of amphotericin B does not improve outcome of primary treatment of invasive aspergillosis. Cancer 2005; 103: 2334-2337.
56.Popp AI, White MH, Quadri T, Walshe L, Armstrong D. Amphotericin B with and without itraconazole for invasive aspergillosis: a three-year retrospective study. Int JInfect Dis 1999; 3: 157-160.
57.Wtdsh TJ, Patterson T, Langston A, et al. Posaeonazole for treatment of invasive aspergillosis in patients who are refractory to or intolerant of conventional therapy: an externally controlled blind trial (abstract) . In :Proceedings 45th ASH, 2006: 682.
58. Raad II, Hanna HA, Boktour M, et al. Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin. Leukemia. 2008 Mar;22(3): 496-503.
59. Alves SH, Da Matta DA, Azevedo AC, et al. In vitro activities of new and conventional antimycotics against fluconazole-susceptible and non-susceptible Brazilian Candida spp. isolates. Mycoses. 2006 May;49(3) : 220-5.。
60. Pasqualotto AC, Denning DW. New and emerging treatments for fungal infections. J Antimicrob Chemother. 2008 Jan;61 Suppl 1:119-30.
61.Mycamine (micafungin) [package insert]. Deerfield,IL:Astellas Pharma US Inc; 2006.
62.Eraxis (anidulafungin) [package insert]. New York,NY:Pfizer Inc;2007.
63. Pasqualotto AC, Denning DW. New and emerging treatments for fungal infections. JAntimicrob Chemother. 2008 Jan;61 Suppl